Stopper assembly having bypass features for use in a multi-chamber syringe barrel

ABSTRACT

A stopper assembly having by-pass features for use in a multi-chamber syringe barrel. The stopper assembly includes a sequential stopper body responsive to fluid forces for enabling the sequential delivery of disparate contents, such as disparate fluids, separately held in the syringe barrel. The sequential stopper body has a generally cylindrical sidewall with a distal end, a proximal end and a longitudinal axis therethrough. The stopper assembly also includes a generally cylindrical flow channelizer mounted to the distal end of the sequential stopper body. The flow channelizer enables the reconstitution of dry medicament held in the syringe barrel distally of the flow channelizer. The flow channelizer features opposed proximal and distal ends and a generally cylindrical outer surface therebetween. At least one fluid flow channel extends between the proximal and distal ends of a flow channelizer. A distally directed, conically-shaped projection is located at the distal end of the flow channelizer to prevent the accumulation of dead space between the channelizer and the internal shoulder located at the distal end of the syringe barrel. The stopper assembly may be employed in a multi-chambered syringe barrel featuring a by-pass channel to permit fluids to pass distally of the stopper assembly. The multi-barreled syringe barrel can be separated into disparate chambers by one or more by-pass stoppers so as to contain disparate components intended for sequential delivery by the stopper assembly.

This is a divisional of application Ser. No. 08/672,788, filed Jun. 28,1996 pending.

I. FIELD OF THE INVENTION

The invention relates to stoppers, and more particularly, to a stopperassembly having bypass features to promote reconstitution of a dry drug,such as a lyophilized drug, held in a hypodermic syringe barrel and thento promote complete sequential injection of disparate contents held inseparate chambers in the syringe barrel.

II. BACKGROUND

As is known in the art, hypodermic syringes include an elongate barrelhaving opposed proximal and distal ends with a chamber therebetween forreceiving a fluid. A passageway extends through the distal end of thesyringe barrel and communicates with the chamber. The distal end of thesyringe barrel is connected to a piercing element, such as a needlecannula or a blunt cannula, for delivering fluid from the chamber andpassageway. The proximal end of the syringe barrel receives a plungerrod and stopper assembly. Force applied to the plunger rod urges thestopper along the barrel to drive liquid from the chamber through theneedle cannula.

Oftentimes, it is desired to deliver from the hypodermic syringe anumber of discrete substances held within the chamber. These discretesubstances normally must be held separate from one another until suchtime as delivery to the patient is desired. Et is necessary, then, thatthe chamber defined between the proximal and distal ends of the elongatebarrel be divided into a discrete number of chambers, each capable ofholding a substance intended for delivery to a patient.

Bearing the foregoing in mind, it would be useful to construct ahypodermic syringe capable of simultaneously storing a medicamenttogether with any components which are to be administered, with theability to keep the medicament and the components separate untiladministration is desired. Medicaments storable in hypodermic syringegscan be in liquid form or in dry form. It is often desirable to storemedicaments in dry form since, depending on the type of medicament, itwill display a longer shelf-life vis-a-vis the liquid form of the drug.As the skilled artisan will appreciate, one way to reduce a liquid drugto dry form is through a lyophilization process. In this process, liquidmedicaments are subjected to a freeze-drying, or lyophilization,process, that reduces the liquid medicament to a dried powder orgranular form. For purposes of simplicity, reference in this patentapplication to a drug in lyophilized form is intended to encompass anydry medicament, all of which require reconstitution prior to delivery.

Frequently, dry medicaments are located in a multi-chamber syringebarrel in the chamber located most adjacent the piercing element. Inorder to administer the medicament to a patient, a diluent is introducedinto the chamber containing the dry medicament in order to reconstitutethe drug into its liquid form. Thereafter, the reconstituted medicamentcan be administered from the same multi-chamber syringe which had storedthe lyophilized medicament. It is also desirable to isolate the drymedicament from the ambient environment until such time asreconstitution and delivery is desired.

With the foregoing objectives in mind, U.S. Pat. No. 4,929,230 toFrederick W. Pfleger ("Pfleger '230"), whose disclosure is specificallyincorporated by reference herein, describes a particular stopperconstruction useful for dividing the syringe barrel into a plurality ofchambers and allowing separate liquid contents held by the syringebarrel to be sequentially administered to a patient. Making particularnumerical reference to components disclosed by Pfleger '230, there isdisclosed a free piston (or stopper) 33 including a hollowed chamber 48facing the end wall 23 of the syringe barrel. Chamber 48 can be realizedas a hollow circularly disposed about the central axis of stopper 33(FIGS. 5, 6, 7) or, as shown in FIGS. 9, 10 or 11, it can assume aflattened, narrow configuration offset from the central axis of thestopper. Stopper 33 includes a closed end 34, which faces away from endwall 23 of the syringe barrel. Closed end 34 has a diameter less thanthe interior diameter of the syringe barrel. A peripheral sidewall 35obliquely extends between closed end 34 of stopper 33 and a cylindricalperipheral sealing surface 36 in contact with the interior surface ofthe syringe barrel. Oblique sidewall 35 overlaps with a portion ofhollowed chamber 48. It is stated at Col. 3, lines 15-17, that theoblique sidewall 35 has its large end generally cylindrical, as thesealing surface 36, for sealing engagement with the syringe barrel, andit is stated at Col. 3, lines 19-23, that external ribs 37 help preventtipping of the piston as it moves in the syringe barrel. It is believedby the inventors herein that the oblique sidewall 35 is itselfcylindrically formed around stopper 33 and, thus, extends about theentire circumference of the stopper. A force is generated by aproximal-most stopper 31 connected to plunger rod 30, stopper 33 willcome to rest adjacent internal shoulder 25 of the syringe barrel.Continued motion by stopper 31 increases the fluid forces exerted uponoblique sidewall 35 to overcome the resilient material sealing forcesinherent in stopper 33. Because of the presence of hollowed chamber 48,oblique sidewall 35 will collapse inwardly, allowing the fluid contentsheld proximally of closed end 34 to proceed in a distal direction fordelivery through the needle cannula.

Pfleger '230 is not particularly suited to an application requiring thereconstitution of a dry drug before the sequential delivery of othercomponents, such as flushes, retained by the syringe barrel. Forinstance, neither the teaching of Pfleger '230, nor the structure ofPfleger '230, is adapted to permit reconstitution of a medicament heldin dry form in a chamber of the syringe barrel. Pfleger '230 is directedtowards sequential delivery of liquid components but not to sequentialdelivery of a dry component.

Moreover, in certain prior art hypodermic syringes, a certain amount ofliquid can remain in the syringe barrel after the stoppers are advancedthe fill length of the barrel during an injection process. There remainsin most syringes a certain residual volume, no matter how small, whichis trapped between the end of the stopper and the needle tip, whichincludes the volume of the needle cannula and the volume presented atthe distal end of the syringe barrel. A quantity of the medication canalso be trapped in the area around and between the sidewalls of thestopper and the interior of the syringe barrel. In the case of expensivemedications and medications requiring extreme precision and delivery,this so-called "dead space" must be overcome by overfilling the barrelin order to ensure that the proper dose is delivered. The additionalmedication will be disposed of with the used syringe. The costsassociated with the dead volume can accumulate substantially. It wouldbe beneficial to prevent waste of medication trapped in the syringebarrel, for instance, as evidenced by Pfleger '230 between hollow end 48of the stopper, internal shoulder 25 located at the extreme distal endof the syringe barrel, and outlet port 24 associated with the syringebarrel. A quantity of medication that can be held between these surfacesis seen, for instance, in FIG. 7 of Pfleger '230.

Accordingly, there is a need for a sequential stopper having bypassfeatures to promote reconstitution of a dry drug held in a syringebarrel and which thereafter allows sequential injection of a series ofdisparate contents held in separate chambers in the syringe barrel, allof which results in reducing the amount of medicament trapped in thesyringe barrel after delivery. Such a stopper is disclosed herein.

III. SUMMARY OF THE INVENTION

A stopper assembly in accordance with the present invention includes twocomponents: (a) a piston-like, sequential stopper body responsive tofluid forces for enabling the sequential delivery of disparate contents,such as disparate fluids, separately held in the syringe barrel in alocation proximal of the sequential stopper body; and (b) a generallycylindrical flow channelizer mounted to the distal end of the sequentialstopper body to enable reconstitution of a dry medicament, such as alyophilized medicament, held in the syringe barrel in a location distalof the flow channelizer and to thereafter enable the sequential deliveryof the disparate fluids held proximally of the sequential stopper bodythrough a fluid passage provided in the syringe barrel.

The stopper assembly in accordance with the present invention may beemployed in a multi-chamber syringe barrel that is configured to retainthe lyophilized medicament as well as the disparate fluids. The stopperassembly may be located adjacent the distal end of the syringe barrel ina manner so as to define a chamber located distally of the flowchannelizer which contains the lyophilized medicament. One or morebypass stoppers may be located proximally of the sequential stopper bodyin a manner to divide the syringe barrel into separate chambers forholding the disparate fluids separate from one another. A bypass channelis provided in the wall of the syringe barrel to permit the disparatefluids to pass sequentially between their respective chambers andthrough fluid flow channels defined on the flow channelizer for deliverythrough the passage of the syringe barrel.

The sequential stopper body has a generally cylindrical sidewall with adistal end, a proximal end, and a longitudinal axis therethrough. Anelongate hollow chamber is disposed within the interior of thesequential stopper body. Preferably, the elongate hollow chamber isdisposed to one side of the longitudinal axis of the sequential stopperbody. The elongate hollow chamber includes a distal end, a proximal end,and may include an opening communicating with the distal end of thesequential stopper body. One or more sealing elements arecircumferentially disposed about the sidewall of the sequential stopperbody. The circumferential sealing elements can be formed as a pluralityof rings circumferentially formed about the piston-like sequentialstopper body.

The stopper assembly of the present invention includes structuredesigned to reconstitute a lyophilized medicine and to directsubstantially all of the fluids held proximally of the stopper assemblyin a distal direction for substantially complete delivery to a piercingelement affixed to the distal end of the syringe barrel. To this end, apair of sealing elements are longitudinally disposed along the sidewallof the sequential stopper body in preferably parallel relation to thelongitudinal axis. The pair of longitudinal sealing elements are eachlocated along the sidewall and separated by a distance at least equal toif not slightly greater than the maximum width defined by the elongatehollow chamber formed within the sequential stopper body.

In a preferred embodiment, the cylindrical sidewall and/or thecircumferential sealing elements of the sequential stopper body arelargely in fluid-tight contact with the interior surface of the syringebarrel. However, a portion of the cylindrical sidewall is recessed fromthe interior surface of the syringe barrel to provide means to exertfluid pressure onto a portion of the circumferential sidewall in orderto cause only that portion of the circumferential sidewall to collapsetowards the hollow chamber, thereby establishing a fluid conduit betweenthe distal and proximal ends of the sequential stopper body. In apreferred embodiment, the recessed portion of the cylindrical sidewallis formed as a sloping surface adjacent the proximal end of the stopperbody that is located between the pair of longitudinal sealing elements.

The flow channelizer includes at least one fluid flow channel extendingbetween the proximal and distal ends of the flow channelizer, In apreferred embodiment, one or more helically oriented flow channels areprovided around the flow channelizer. The fluid flow channelscommunicate fluid passing distally of the sequential stopper assembly tothe passage of the syringe barrel. A distally directed, substantiallyconically-shaped projection is located on the distal end of the flowchannelizer. The distally-directed, conically-shaped projection can bedimensioned to substantially conform to the shape assumed by theinternal shoulder located at the distal end of the syringe barrel.

In use, fluid force exerted upon the proximal-end of the sequentialstopper body causes the sequential passage of the disparate fluids thatare held proximally of the sequential stopper body through the fluidchannel of the syringe barrel and the flow channels of the flowchannelizer. The medicament is thus reconstituted in and delivered fromthe chamber located distally of the flow channelizer. Continued fluidpressure on the proximal end of the sequential stopper body willeventually cause the flow channelizer to seat adjacent the distal end ofthe syringe barrel. The distally-directed, conically-shaped projection,conforming substantially to the shape of the internal shoulder locatedat the distal end of the syringe barrel, prevents excessive accumulationof fluid in that area.

Once the flow channelizer is seated against the distal end of thesyringe barrel, increasing fluid force exerted on the recessed portionof the cylindrical sidewall of the sequential stopper body causes theportion of sidewall located between the longitudinal sealing elements tocollapse towards the hollow chamber. The collapse of the sidewall inthis area initiates a fluid conduit between the proximal and distal endsof the sequential stopper body restricted generally to that portion ofthe cylindrical sidewall of the sequential stopper body located betweenthe longitudinal sealing elements to enable the sequential delivery of asecond liquid held proximally of the stopper assembly. The longitudinalsealing elements themselves, together with the portion of thecircumferential sealing elements not located between the longitudinalsealing elements, remain in fluid-tight contact with the syringe barrel.Accordingly, fluid is substantially prevented from accumulating aroundthe cylindrical sidewalls of the sequential stopper body or between thedistally-directed conically shaped projection and the correspondingdistal end of the syringe barrel, such that fluid is substantiallyentirely directed through the fluid conduit for delivery through thefluid flow channels of the flow channelizer and out of piercing elementattached to the distal end of the syringe barrel.

IV. BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described in more detail by way of referenceto the appended drawings, wherein:

FIG. 1 is a perspective view of a syringe assembly employing the stopperassembly in accordance with the present invention;

FIG. 2 is an exploded perspective view of the stopper assembly inaccordance with the present invention, illustrating both the sequentialstopper body and the flow channelizer;

FIG. 3 is a cut-away view of the stopper assembly of the presentinvention, taken along line 3--3 of FIG. 2;

FIG. 3A depicts another way of providing a recess in the sidewall of thesequential stopper body;

FIG. 4 is a bottom view of the sequential stopper body depicted in FIG.2;

FIG. 5 is a top view of the sequential stopper body depicted in FIG. 2;

FIG. 6 is a cross-sectional view of the syringe assembly of FIG. 1before beginning an injection sequence, illustrating the syringeassembly holding medicament in its lyophilized form as well as disparatecontents held in separate chambers;

FIG. 7 is a second cross-sectional view of the syringe assembly of FIG.1, illustrating the delivery of a diluent from one of the separatechambers through the bypass channel of the syringe barrel and the fluidflow channel of the flow channelizer to reconstitute the lyophilizedmedicament during an injection sequence;

FIG. 8 is a third cross-sectional view of the syringe assembly of FIG.1, illustrating the delivery of the now-reconstituted medicament fromthe passage of the syringe barrel and the distal movement of a flushagent from its chamber into the adjacent chamber formerly occupied bythe diluent;

FIG. 9 is a fourth cross-sectional view of the syringe assembly of FIG.1, illustrating the full location of the flush agent in the chamberformerly occupied by the diluent;

FIG. 10 is a fifth cross-sectional view of the syringe assembly of FIG.1, illustrating full seating of the flow channelizer against the distalend of the syringe barrel and the collapse of the cylindrical sidewallof the sequential stopper body between the longitudinal sealingelements, to establish a fluid conduit between the proximal and distalends of the sequential stopper body such that the flush agent isdelivered to the fluid flow channels of the flow channelizer fordelivery through the passage of the syringe;

FIG. 11 is a sixth cross-sectional view of the syringe assembly of FIG.1, illustrating the end of the injection sequence; and

FIG. 12 is a partial cross-sectional view of the syringe assembly ofFIG. 1, illustrating the placement of the various components at the endof the injection sequence.

V. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

A convention used in this patent application is that the term "distal"refers to an end closer to the needle end of a syringe barrel, whereasthe term "proximal" refers to an end farther away from the needle end ofthe syringe barrel.

Turning now to the drawings, wherein like numerals denote likecomponents, FIGS. 2-5 denote one embodiment 200 of the stopper assemblyin accordance with the present invention. FIGS. 1 and 6-12 illustratestopper assembly 200 in conjunction with a multi-chambered syringebarrel 100. FIGS. 6 -12 particularly illustrate use of stopper assembly200 in reconstituting a lyophilized medicament "M" held distally of thestopper assembly, together with the sequential delivery of disparatecontents held in separate chambers defined proximally of stopperassembly 200.

For ease of explanation, particulars of stopper assembly 200 will beexplained first. Thereafter, use of the stopper assembly in conjunctionwith the multi-chambered syringe barrel will ensue.

Turning then to FIGS. 2-5, stopper assembly 200 includes a sequentialstopper body 201 and a flow channelizer 225. Sequential stopper body 201includes a proximal end 204, a distal end 206, and a cylindricalsidewall 202 extending therebetween. The sequential stopper body ischaracterized by longitudinal axis 208. Likewise, flow channelizer 225features a proximal end 226, a distal end 228, and one or more fluidflow channels 238 extending therebetween. The construction of flowchannelizer 225 is analogous to that described in U.S. patentapplication Ser. No. 5,489,266 "Syringe Assembly and Method forLyophilizing and Peconstituting Injectable Medication", whose disclosureis specifically incorporated by reference herein.

FIGS. 2-5 illustrate that stopper assembly 200 is formed in separatecomponents, viz., a sequential stopper body 201 and a flow channelizer225, that are connected cooperative mating structure. For example, aprotrusion 242 can be provided from distal end 206 of the sequentialstopper body that is configured for insertion into an aperture 240 thatis defined on distal end 226 of the flow channelizer. The protrusion caninclude a groove 244 configured to mate with one or more nubs 246defined within the aperture. Of course, it will be understood that theplacement of the protrusion and aperture can be reversed betweensequential stopper body 201 and flow channelizer 225, as can be thelocation of the groove and nubs. The resulting connection will result insecure fixation of sequential stopper body 201 to flow channelizer 225.Other cooperative structure for securing the sequential stopper body tothe flow channelizer, such as by adhesively bonding, is also within thepurview of the invention. Furthermore, if desired, sequential stopperbody 201 and flow channelizer 225 can be configured for releasablemating contact, such as by providing a threaded interface betweenprotrusion 242 and aperture 240. Likewise, if desired, stopper assembly200 can be formed in a unitary manner from one component, in lieu ofseparating providing the sequential stopper body 201 from flowchannelizer 225.

Turning now more particularly to sequential stopper body 201, aplurality of sealing elements may be provided on the sequential stopperbody for sliding fluid-tight contact between the sequential stopper bodyand the interior surface 140 of syringe barrel 100 (see FIGS. 1 and6-12). One or more circumferentially disposed sealing elements 210 areprovided about cylindrical sidewall 202. In the embodiment depictedherein, four such of circumferential sealing elements 210a, b areprovided. Here, a proximal-most circumferential sealing element 210b islocated adjacent proximal end 204 of the sequential stopper body, suchthat fluid can be prevented from accumulating between cylindricalsidewall 202 and interior surface 140 of syringe barrel 100 in the areaproximal of circumferential sealing elements 210a, themselves locatedintermediate the proximal and distal ends of sequential stopper body201. It will be realized by the skilled artisan that any number ofcircumferential sealing elements may be chosen according to the size ofthe stopper or as need or desire dictate.

Sequential stopper body 201 includes an elongate hollow chamber 220disposed in a direction which is preferably substantially parallel tolongitudinal axis 208. As best seen in FIG. 3, the elongate hollowchamber 220, which can assume a flattened shape, is preferably notconcentric with longitudinal axis 208 and is preferably disposedadjacent cylindrical sidewall 202. Hollow elongate chamber 220 featuresa proximal end 221 located within the interior of the sequential stopperbody and a distal end 223. The purpose of elongate hollow chamber 220 isanalogous to hollow chamber 48 of Pfleger '230, as previously discussed.As here shown, it is envisaged that owing to mold tooling conventionallyemployed to form sequential stopper body 100, distal end 223 of thechamber will communicate with distal end 206 of sequential stopper body201 via an opening 222. However, it will be understood by the skilledartisan that elongate chamber 220 can be formed by other ways such thatit is entirely within the sequential stopper body without an opening222.

A feature of stopper assembly 200 in accordance with the presentinvention is that it features structure designed to minimize a quantityof medicament which would be trapped between stopper assembly 200 andsyringe barrel 100, and which would be otherwise wasted when the syringebarrel were disposed of following use. To this end, sequential stopperbody 201 features a pair of longitudinal sealing elements 212 preferablydisposed on cylindrical sidewall 202 in substantially parallelrelationship with longitudinal axis 208. As best seen in FIGS. 2, 4 and5, longitudinal sealing elements 212 are spaced from one another oncylindrical sidewall 202 by a distance "Y" that is at least equal to, ifnot slightly greater than, a maximum width "W" displayed by elongatehollow chamber 220. For the purposes of this patent application, areference to a portion or an area of cylindrical sidewall 202 that islocated between longitudinal sealing elements 212 shall mean thatportion or area of cylindrical sidewall 202 which is encompasses bydistance "Y" separating the longitudinal sealing elements.

As will be evident in ensuing discussion of the operation of stopperassembly 200 in an injection sequence (FIGS. 6-12), upon full seating offlow channelizer 225 against internal shoulder 302 of the syringebarrel, it will be required to initiate a fluid conduit between theproximal and distal ends 204, 206 of sequential stopper body 201 suchthat a last remaining disparate contents held proximally of stopperassembly 200 will be permitted to pass between the proximal and distalends of the sequential stopper body and through the channels 238 of flowchannelizer 225 for delivery through passage 108 of syringe 100 (seeFIGS. 10-12). To this end, it is an aspect of stopper assembly 200 inaccordance with the present invention to initiate a fluid conduit 310between the proximal and distal ends of the sequential stopper body onlyin the area of cylindrical sidewall 202 located between longitudinalsealing elements 212. Sequential stopper body 201 is itself disposed forsliding, fluid-tight relationship with interior surface 140 of syringebarrel 100--as here depicted, by the sliding fluid-tight relationshipbetween circumferential sealing elements 210a, b and interior surface140 of the syringe barrel. One way to initiate fluid conduit 310 is tospace a portion of cylindrical sidewall 202 that is adjacent proximalend 204 and between longitudinal sealing elements 212, such that thisportion of the cylindrical sidewall is not in fluid-tight contact withinterior surface 140 of the syringe barrel. In this way, fluid force canact upon the portion of cylindrical sidewall 202 located between sealingelements 212 to collapse that portion of the sidewall towards hollowchamber 220.

One way to space a portion of cylindrical sidewall 202 from interiorsurface 140 of syringe barrel 100 is to provide a recess 215 in thesidewall, substantially aligned with longitudinal axis 208, in an arealocated between longitudinal sealing elements 212 and adjacent proximalend 204 (see FIG. 3A). In the embodiment of the stopper assemblydepicted in FIGS. 1-3, the sidewall is spaced from the interior surfaceof the syringe barrel by providing a sloping surface 214 on cylindricalsidewall 202, adjacent proximal end 204 of the stopper, in an areabetween the longitudinal sealing elements. Sloping surface 214 extendsobliquely outwardly on cylindrical sidewall 202 from proximal end 204 tothe proximal-most of circumferential sealing elements 210a. Thegoverning consideration is that a portion of the sidewall be spaced fromthe interior surface of the syringe barrel in order that fluid haveaccess to that area of the sidewall. It will be noted that because ofthe presence of recess 215 or sloping surface 214, circumferentialsealing element 210b is only partially circumferentially disposed aboutthe sequential stopper body such that it does not extend betweenlongitudinal sealing elements 212.

A further feature of the stopper assembly 200 in accordance with thepresent invention, is that it prevents the accumulation of fluid betweendistal end 228 of flow channelizer 225 and internal shoulder 302associated with syringe barrel 100 (see FIGS. 6-12). To this end, flowchannelizer 225 features a distally directed, conically-shapedprojection 230 on distal end 228. While here depicted as a conus, itwill be realized that conically-shaped projection 230 can assume anyshape generally approaching a conus. Conically-shaped projection 230 ischaracterized by a base 236 intersecting with distal end 228 of the flowchannelizer, and features a peaked tip 234 and a wall portion 235extending between the peaked tip and the base. It will be noted that theshape and dimensions of distally directed, conically-shaped projection230 are preferably shaped to conform to the shape assumed by distalshoulder 302 in a manner to minimize any dead space between them whichwould otherwise trap fluid.

It will be appreciated by the skilled artisan that it may be difficultto control the shape or dimensions associated with certain portions ofsyringe barrel 100. For instance, one area particularly difficult tocontrol is the shape of the bottom of the syringe barrel such as atinternal shoulder 302. Accordingly, if desired, structure can beincorporated on conically-shaped projection 230 to account for anytolerance or shape differences at distal shoulder 302. Referring to FIG.2, conically-shaped projection 230 can optionally feature one or morediscontinuities, such as one or more raised ribs 250 which act toprevent immediate sealing of fluid passage 108 in the area of internalshoulder 302. Accordingly, any liquid trapped in the dead space betweendistal shoulder 302 and conically-shaped projection 230 can run alongraised ribs 250 through fluid passage 108 for delivery by needle cannula400 attached to distal tip 104 of syringe barrel 200 (see FIGS. 6-12).The raised ribs can be designed so as to tend to collapse at the end ofthe injection phase, permitting substantially full surface contactbetween wall portion 235 of the conical projection anb distal shoulder302 of the syringe barrel to insure that nothing remains trapped betweenthem. It will be understood by the skilled artisan that grooves may beemployed in lieu of, or in combination with, ribs 250.

Turning now to FIGS. 6-12, operation of stopper assembly 200 inconjunction with multi-chambered syringe barrel 100 will now beexplained. Syringe barrel 100 features an open proximal end 102, aclosed distal end 104, and a substantially cylindrical chamber wall 106extending therebetween. Distal shoulder 302 is located adjacent closeddistal end 104. Syringe barrel 100 (more specifically chamber wall 106)includes the aforementioned interior surface 140 that defines afluid-receiving compartment within the syringe barrel. Stopper assembly200 is preferably located within syringe barrel 100 at a locationintermediate proximal and distal ends 102, 104, such as to define achamber 130 distally of flow channelizer 225 that contains a quantity oflyophilized medicament "M" intended to be reconstituted. A cannulaassembly 400 may be attached in a conventional manner to distal end 104of the syringe barrel such that it is in communication with syringepassage 108. It will be realized that if desired, various sealing meansmay be incorporated in passage 108 and/or with needle cannula 400 toisolate medicament "M" until such time as injection is desired.

Proximally of sequential stopper body 201, syringe barrel 100 isseparated into one or more separate chambers, each capable of holdingdisparate components in isolation until such time as an injectionsequence begins. In the embodiment depicted herein, the portion ofsyringe barrel 100 located proximally of sequential stepper body 201 isseparated into two chambers 132, 134 by a dividing by-pass stopper 120.Bypass stopper 120 includes a proximal end 122, a distal end 121 and maybe of conventional construction for sliding, fluid-tight relation withinterior surface 140 of the syringe barrel. Chamber 132 may contain adiluent "D" which will be used to reconstitute lyophilized medicament"M", while chamber 134 may contain a flush agent "F" which will helpremove substantially all of reconstituted medicament ("M+D") from thesyringe barrel so that it can be delivered through passage 108. As willbe evident to the skilled artisan, by suitably configuring thedimensions of the syringe barrel and its components, as well as thelocation of by-pass 110 on the syringe barrel (see below), the portionof syringe barrel 100 located proximally of sequential stopper body 201can be divided into as many separate chambers as desired, andconsequently holding the the desired number of disparate substances, byemploying an appropriate number of by-pass stoppers 120.

In order to exert force during the injection phase, a plunger stopper114 is located within syringe barrel 100 in sliding fluid-tight relationwith interior surface 140. A plunger rod 116 may be threadably connectedto plunger stopper 114, with a thumb plate 118 provided at the other endof plunger rod 116. A flange 107 can be formed around open proximal end102 of the syringe barrel to enable digital manipulation of the syringebarrel during use.

Syringe barrel 100 features a by-pass 110 in cylindrical sidewall 106 ofthe syringe barrel. By-pass 110 defines a fluid by-pass channel 112.Fluid by-pass channel 112 provides a break in what would otherwise becomplete fluid-tight contact between circumferential sealing elements210a, b of the sequential stopper body (as well as sealing elementsassociated with bypass stopper 120) and interior surface 140 of thesyringe barrel as stopper assembly 200 and bypass stopper 120 are urgedin the distal direction towards shoulder 302. Fluid bypass channel 112permits the passage of fluid held proximally of the sequential stopperbody into the medicament chamber 130 via the fluid flow channels 238established within a fluid channelizer 225.

As will become more evident hereinbelow, the dimensions of the variouscomponents and their placement within syringe barrel 100 is such thatby-pass channel 112 serves as a fluid conduit or all of fluid heldproximally of sequential stopper body 201 apart from the proximal-mostof the fluids held within the syringe barrel. Here, the proximal-most ofthe fluids is denoted by flush agent "F" located within chamber 134. Atsuch time as all of the fluids, apart from the proximal-most of thefluids, has been urged into medicament chamber 130 and out passage 108,the proximal-most of the retained fluids will be located in the syringebarrel at a point distal of by-pass channel 112. At this point, fluidpressure will be exerted upon sloping surface 214 of sequential stopperbody 201 to open fluid conduit 310, as hereinafter described.

Explaining now the sequence of an injection employing a stopper assembly200 in accordance with the present invention, in FIG. 6, syringe 100includes a charge of lyophilized medicament "M" in chamber 130. A chargeof a diluent "D" is located in a chamber 132 defined within syringebarrel 100. A charge of flush agent "F" is located in a chamber 134,delimited from chamber 132 via by-pass stopper 120. Plunger stopper 114is located at the proximal limit of chamber 134.

In FIG. 7, a user has begun an injection sequence by beginning to moveplunger rod 116 in the direction "Z". The force exerted by the user uponplunger rod 116 causes plunger stopper 114 to move flush agent "F",by-pass stopper 120, diluent "D" and stopper assembly 200 in a distaldirection. At some stage of the injection sequence, circumferentialsealing elements 210 will encounter by-pass channel 112. This will openby-pass channel 112 to diluent "D", allowing diluent "D" to pass throughby-pass channel 112 and pass through fluid flow channels 238 of the flowchannelizer to enter the medicament chamber 130. The helical arrangementof fluid flow channels 238 causes a swirling action of the diluent "D"entering within medicament chamber 130. The swirling of diluent "D"promotes full reconstitution of the charge of medicament "M". As soon asall of diluent "D" has been transferred into medicament chamber 230,proximal end 204 of the sequential stopper body and distal end 121 ofthe bypass stopper will be in contact. At this point, owing tocontinuing, distally directed force on the bypass stopper, stopperassembly 200 will move distally to commence injection of thereconstituted medicament "M+D".

FIG. 8 illustrates a user's continued exertion of plunger rod 11 6 indirection Z. It will be noted that stopper assembly 200 has passedcompletely distally of by-pass channel 112, while proximal end 122 ofby-pass stopper 120 has passed just distally of the onset of by-passchannel 112. At this point, reconstituted medicament "M+D" in chamber230 continues to be delivered through passage 108 of syringe barrel 100.At the same time, flush agent "F" passes from chamber 134 throughby-pass channel 112 to enter chamber 132 that formerly contained diluent"D".

FIG. 9 illustrates continued injection of reconstituted medicament"M+D". Flow channelizer 225 is not yet seated against distal internalshoulder 302 of the syringe barrel. Continued distal motion "Z" ofplunger rod 116 has forced all of flush agent "F" into chamber 132, suchthat proximal end 122 of the by-pass stopper and plunger stopper 114 arenow in contact.

FIG. 10 illustrates substantial completion of the injection phaseinvolving reconstituted medicament "M+D". It will be seen that flowchannelizer 225 is now seated adjacent distal shoulder 302 of thesyringe barrel. Force continues to be urged upon plunger stopper114/by-pass stopper 120, pushing the charge of flush agent "F" againstsequential stopper body 201. It will be noted that at this point, thedimensions of the various components are such that stopper assembly 200is located distally of bypass channel 112, such that circumferentialsealing elements 210 of the sequential stopper body are in full contactwith interior surface 140 of the syringe barrel. In order to expel flushagent "F", it is necessary to create fluid conduit 310 within sequentialstopper body 201.

Referring to FIGS. 2-5 and 10-12, after conically-shaped projection 230is seated adjacent internal shoulder 302 of syringe barrel 100,continued fluid force exerted upon proximal end 204 of the sequentialstopper body will be directed to the area of sloping surface 214. Theabsence of circumferential sealing element 210b between longitudinalsealing elements 212 causes fluid (here, flush agent "F") to exert forceupon sloping surface 214. It will be noted that circumferential sealingelements 210 (particularly proximal-most circumferential sealing element210b) and longitudinal sealing elements 212 remain in sealing contactwith interior surface 140 of the syringe barrel, in a manner to preventfluid from being directed between interior surface 140 of the syringebarrel and cylindrical sidewall 202 of the sequential stopper body.

The continued fluid force exerted by flush agent "F" upon slopingsurface 214 causes the sloping surface to collapse towards elongatedhollowed chamber 220. Collapse of sloping surface 214 towards thehollowed chamber urges collapse of the portion of sidewall 202 betweenthe longitudinal sealing elements. Particularly, sections 210c ofcircumferential sealing elements 210a (sections 210c are the portions ofcircumferential sealing elements 210a disposed between longitudinalsealing elements 212) will also separate from contact with the interiorsurface 140 of syringe barrel 100. By insuring that longitudinal sealingelements 212 are separated a sufficient distance "Y" with respect tomaximum width "W" of chamber 220, longitudinal sealing elements 212 willthemselves remain of substantial fluid-tight contact with interiorsurface 140 of the syringe barrel. As seen in FIGS. 10-12, the effect ofthe collapse of sloping surface 114 and separation of sections 210c frominterior surface 140 of the syringe barrel is to create a fluid conduit210 between the proximal and distal ends 204, 206 of the sequentialstopper body. Fluid conduit 310 is substantially restricted to an areaof sidewall 202 defined between longitudinal sealing elements 212. Flushagent "F" located proximally of sequential stopper body 201 will thuspass through fluid conduit 310 and enter fluid flow channels 238 of flowchannelizer 225. Flush agent "F" will pass distally of channelizer 225for delivery through passage 108. Flush agent "F" serves to remove theresidual reconstituted medicament "M+D" remaining in chamber 130, suchthat the reconstituted medicament is substantially fully delivered tothe patient. Flush agent "F" located proximally of sequential stopperbody 201 can only pass distally of the sequential stopper body via fluidconduit 310. By preventing the accumulation of fluid between cylindricalsidewall 202 of the sequential stopper body and interior surface 140 ofthe syringe barrel, and by substantially eliminating dead space betweendistal shoulder 302 of the syringe barrel and distal end 228 of the flowchannelizer, and by providing a single fluid conduit 310 between theproximal and distal end of the sequential stopper body, substantiallyall of the fluid held proximally of the stopper assembly directeddistally through a passage 208 delivery by piercing element 400.

The longitudinal and circumferential sealing elements of sequentialstopper body 210 can be made from the same material forming thesequential stopper body. The sequential stopper body 201 and flowchannelizer 225 are preferably formed from suitable elastomericmaterials, such as rubbers or thermoplastic elastomers or othermaterials known to the skilled artisan that are suitable for formingsyringe stoppers. The same will be true of by-pass stopper 120 andplunger stopper 114. The various stoppers and their associatedcomponents can be formed to suitable dimensions to accommodate varioussizes of syringes encountered in practice. It will also be appreciatedby the skilled artisan that various lubricating treatments, such assiliconizing treatments, various coating treatments such as sprayingtreatments, or various filming treatments such as PTFE filmingtreatments, can be applied to any of the stoppers to improve slidingperformance within the syringe barrel as need or desire dictate.

It will be appreciated and understood by those skilled in the art thatfurther and additional forms of the invention may be devised withoutdeparting from the spirit and scope of the appended claims, theinvention not being limited to the specific embodiments shown.

We claim:
 1. A syringe assembly for enabling reconstitution of a drymedicament held in the syringe assembly and for enabling subsequent,substantially complete delivery of disparate contents held by thesyringe assembly, comprising:a syringe barrel having an open proximalend, a distal end and a substantially cylindrical chamber wall extendingtherebetween to define a fluid receiving compartment, said fluidreceiving compartment separated into at least two separate chambers forholding separately said disparate contents, a passage extending throughsaid distal end; a plunger stopper dimensioned for sliding fluid-tightengagement with the fluid receiving compartment of said syringe barrel,said plunger stopper having opposed proximal and distal ends; a stopperassembly to enable the reconstitution of said dry medicament and thesubsequent, substantially complete delivery of the disparate contentsheld by the syringe barrel, the stopper assembly located in said fluidreceiving compartment at a location distal from the plunger stopper, thestopper assembly comprising (a) a sequential stopper body responsive tofluid forces for enabling the sequential delivery of said disparatecontents held separately in the syringe barrel, said sequential stopperbody having a generally cylindrical sidewall with a distal end, aproximal end, and a longitudinal axis therethrough and (b) a generallycylindrical flow channelizer mounted to distal end of the sequentialstopper body to enable reconstitution of the dry medication held in thesyringe barrel, said flow channelizer having opposed proximal and distalends and a generally cylindrical outer surface extending therebetween,at least one fluid flow channel extending between said proximal anddistal ends of said flow channelizer, and a distally directed,conically-shaped projection located on the distal end of the flowchannelizer; said dry medicament held in the syringe barrel distally ofthe flow channelizer; at least one bypass stopper located intermediatethe plunger stopper and the stopper assembly to separate the fluidreceiving compartment into said at least two separate chambers; and abypass channel provided in the cylindrical sidewall of the syringebarrel to enable said disparate contents held by said at least twoseparate chambers to pass distally of said stopper assembly for deliverythrough the passage at the distal end of the syringe barrel.
 2. Thesyringe assembly of claim 1, wherein said sequential stopper and saidflow channelizer are formed as a unitary component.
 3. The syringeassembly of claim 1, wherein said sequential stopper and said flowchannelizer include cooperative structure such that said sequentialstopper body is attached to said flow channelizer.
 4. The syringeassembly of claim 1, wherein at least one of the disparate contents heldin said syringe barrel passes through the bypass channel to mix withsaid dry medicament held distally of the stopper assembly toreconstitute the dry medicament for delivery through the passage at thedistal end of the syringe barrel.
 5. The syringe assembly of claim 1,wherein said sequential stopper body comprises:an elongate hollowchamber disposed within said sequential stopper body, said hollowchamber having a distal end, a proximal end and a width; at least onecircumferential sealing element circumferentially disposed about thecylindrical sidewall of the sequential stopper body for sealingengagement with the inside surface of the syringe barrel; a pair oflongitudinal sealing elements longitudinally disposed along the sidewallof the sequential stopper body in parallel relation to the longitudinalaxis for sealing engagement with the inside surface of the syringebarrel, said pair of longitudinal sealing elements separated along thesidewall by a distance at least equal to the width of the hollowchamber; and a recessed surface provided on the cylindrical sidewall ofthe sequential stopper body, said recessed surface located adjacent theproximal end of the sequential stopper body and between the pair oflongitudinal sealing elements; wherein when the flow channelizer isseated against the distal end of the syringe barrel, continuing fluidpressure exerted upon the recessed surface by the disparate contentsheld proximally of the sequential stopper body will allow the portion ofsidewall located between the pair of longitudinal sealing elements tocollapse towards said hollow chamber, said longitudinal sealing elementsthemselves remaining in fluid tight contact with the syringe barrel, toprovide a fluid conduit between the proximal and distal ends of thesequential stopper body limited to that portion of the sidewall betweenthe longitudinal sealing elements to direct substantially all of theremaining disparate contents held proximally of the sequential stopperbody towards said at least one fluid channel of said flow channelizer.6. The syringe assembly of claim 1, wherein said at least one fluid flowchannel includes a plurality of fluid flow channels.
 7. The syringeassembly of claim 6, wherein said plurality of fluid flow channels arehelically oriented around said flow channelizer from said distal endthereof to said proximal end thereof.
 8. The syringe assembly of claim1, wherein the distal end of the syringe barrel includes a shoulder,said conical projection at the distal end of the flow channelizerdimensioned to substantially conform to said shoulder.
 9. The stopperassembly of claim 1, wherein said stopper assembly is formed of anelastomeric material selected from the group consisting of rubbers orthermoplastic elastomers.